Human plasminogen, which functions to maintian blood fluidity by dissolving fibrin clots, is a protein with a molecular weight of 85,000 daltons. On activation, it is converted to plasmin, which consists of heavy (MW 55,000 daltons) and light (MW 25,000 daltons) chain connected by two disulfide bonds. The light chain is similar in sequence to trypsin and contains the active site. The function of the heavy chain is unknown. Recent sequence studies in this and other laboratories have shown that the heavy chain consists of five mutually homologous domains which are characterized by three inter-domain disulfide bonds. It is our goal to elucidate the structure of plasmin(ogen) and to learn how plasminogen interacts with other macromolecules in the fibrinolysis system. Since the primary structure is now almost completely known, we are attempting to obtain information about the tertiary structure of the molecule by chemical modification of amino acids (lysine, tyrosine, tryptophan, aspartic and glutamic acids) exposed on the surface. We are particularly interested to see whether the monologous domains, which have similar primary structures, have similar tertiary structures. In addition we are studying the nature of the lysine binding site in the heavy chain using chemical modification and analog binding studies in order to determine lysine binding is related to the binding to fibrinogen and other plasma proteins.